bims-mikwok 2023-02-19 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒02‒19
fourteen papers selected by
Avinash N. Mukkala, University of Toronto

The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.
Cone photoreceptors transfer damaged mitochondria to Müller glia.
Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.
ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.
Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.
Cytoskeletal association of ATP citrate lyase controls the mechanodynamics of macropinocytosis.
Mitochondrial quality control in acute kidney disease.
Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation.
Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline.
The role of the mechanistic target of rapamycin complex 1 in the regulation of mitochondrial adaptation during skeletal muscle atrophy under denervation or calorie restriction in mice.
ERK1/2-dependent TSPO overactivation associates with the loss of mitophagy and mitochondrial respiration in ALS.
Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery.
Mitochondrial respiration reduces exposure of the nucleus to oxygen.
Mitochondria transfer reverses the inhibitory effects of low stiffness on osteogenic differentiation of human mesenchymal stem cells.

J Cell Biol. 2023 Apr 03. pii: e202204021. [Epub ahead of print]222(4):

The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.

Mehmet Oguz Gok, Olivia M Connor, Xun Wang, Cameron J Menezes, Claire B Llamas, Prashant Mishra, Jonathan R Friedman.

Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.

DOI: https://doi.org/10.1083/jcb.202204021
Cell Rep. 2023 Feb 15. pii: S2211-1247(23)00126-2. [Epub ahead of print]42(2): 112115

Cone photoreceptors transfer damaged mitochondria to Müller glia.

Rachel A Hutto, Kaitlyn M Rutter, Michelle M Giarmarco, Edward D Parker, Zachary S Chambers, Susan E Brockerhoff.

  Mitochondria are vital organelles that require sophisticated homeostatic mechanisms for maintenance. Intercellular transfer of damaged mitochondria is a recently identified strategy broadly used to improve cellular health and viability. Here, we investigate mitochondrial homeostasis in the vertebrate cone photoreceptor, the specialized neuron that initiates our daytime and color vision. We find a generalizable response to mitochondrial stress that leads to loss of cristae, displacement of damaged mitochondria from their normal cellular location, initiation of degradation, and transfer to Müller glia cells, a key non-neuronal support cell in the retina. Our findings show transmitophagy from cones to Müller glia as a response to mitochondrial damage. Intercellular transfer of damaged mitochondria represents an outsourcing mechanism that photoreceptors use to support their specialized function.

Keywords:  CP: Neuroscience; Müller glia; mitochondria; mitophagy; photoreceptor; retina; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2023.112115
Lab Invest. 2022 09;pii: S0023-6837(22)00274-4. [Epub ahead of print]102(9): 979-988

Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.

Baoxiang Li, Limin Liu.

Abnormal Drp1 activation and subsequent excessive mitochondrial fission play a critical role in ischemia-reperfusion injury (I/RI). Although fibroblast growth factor 21 (FGF21) protects organs against I/RI and regulates metabolism, which indicates that FGF21 is involved in mitochondria homeostasis, the detailed mechanism remains unclear. Herein, we investigated whether FGF21 had an effect on Drp1 activation during skeletal muscle I/RI. Drp1 phosphorylation and its translocation to mitochondria, as regulated by FGF21, was examined in mouse and C2C12 cell I/RI models. Mice overexpressing FGF21 displayed alleviation of serum index, histological lesions and apoptosis levels. Moreover, FGF21 markedly decreased cyclin-dependent kinase 1 (CDK1) and Drp1 phosphorylation at Ser616, accompanied by reduced accumulation in mitochondria. In parallel in vitro studies, cells with FGF21 knockdown displayed enhanced Drp1 activation, and the reverse effect was found when FGF21 was added. More importantly, FGF21 attenuated mitochondrial fission with linear mitochondria rather than fragmented mitochondria. Furthermore, a CDK1 inhibitor reduced Drp1 activation and mitochondrial fission due to FGF21 knockdown. This study shows that FGF21 inhibits Drp1 activation to protect mitochondria from fission, thereby rescuing cells from I/RI-induced apoptosis. Our findings may provide a new therapeutic approach to ameliorate skeletal muscle I/RI.

DOI: https://doi.org/10.1038/s41374-022-00787-7
Lab Invest. 2022 01;pii: S0023-6837(22)00107-6. [Epub ahead of print]102(1): 69-79

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

Kailiang Zhang, Rong Bao, Fengyuan Huang, Kevin Yang, Yishu Ding, Lothar Lauterboeck, Masasuke Yoshida, Qinqiang Long, Qinglin Yang.

Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.

DOI: https://doi.org/10.1038/s41374-021-00670-x
FASEB J. 2023 03;37(3): e22805

Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.

Xiaosheng Yang, Yang Liu, Weijie Zhong, Yi Li, Wenchuan Zhang.

  Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.

Keywords:  AFG3L2; Ca2+ levels; Netrin-1; ischemia-reperfusion injury; mitochondrial ROS; phosphorylated AKT

DOI:  https://doi.org/10.1096/fj.202201739R
Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2213272120

Cytoskeletal association of ATP citrate lyase controls the mechanodynamics of macropinocytosis.

Joseph Puccini, Jia Wei, Liang Tong, Dafna Bar-Sagi.

  Macropinocytosis is an actin-dependent mode of nonselective endocytosis that mediates the uptake of extracellular fluid-phase cargoes. It is now well recognized that tumor cells exploit macropinocytosis to internalize macromolecules that can be catabolized and used to support cell growth and proliferation under nutrient-limiting conditions. Therefore, the identification of molecular mechanisms that control macropinocytosis is fundamental to the understanding of the metabolic adaptive landscape of tumor cells. Here, we report that the acetyl-CoA-producing enzyme, ATP citrate lyase (ACLY), is a key regulator of macropinocytosis and describes a heretofore-unappreciated association of ACLY with the actin cytoskeleton. The cytoskeletal tethering of ACLY is required for the spatially defined acetylation of heterodimeric actin capping protein, which we identify as an essential mediator of the actin remodeling events that drive membrane ruffling and macropinocytosis. Furthermore, we identify a requirement for mitochondrial-derived citrate, an ACLY substrate, for macropinocytosis, and show that mitochondria traffic to cell periphery regions juxtaposed to plasma membrane ruffles. Collectively, these findings establish a mode of metabolite compartmentalization that supports the spatiotemporal modulation of membrane-cytoskeletal interactions required for macropinocytosis by coupling regional acetyl-CoA availability with dynamic protein acetylation.

Keywords:  actin cytoskeleton; macropinocytosis; membrane ruffling

DOI:  https://doi.org/10.1073/pnas.2213272120
J Nephrol. 2023 Feb 17.

Mitochondrial quality control in acute kidney disease.

Jingyi Sheng, Xian Li, Juan Lei, WeiHua Gan, Jiayu Song.

  Acute kidney disease (AKD) involves multiple pathogenic mechanisms, including maladaptive repair of renal cells that are rich in mitochondria. Maintenance of mitochondrial homeostasis and quality control is crucial for normal kidney function. Mitochondrial quality control serves to maintain mitochondrial function under various conditions, including mitochondrial bioenergetics, mitochondrial biogenesis, mitochondrial dynamics (fusion and fission) and mitophagy. To date, increasing evidence indicates that mitochondrial quality control is disrupted when acute kidney disease develops. This review describes the mechanisms of mitochondria quality control in acute kidney disease, aiming to provide clues to help design new clinical treatments.

Keywords:  Acute kidney disease; Mitochondria; Mitochondria quality control

DOI:  https://doi.org/10.1007/s40620-023-01582-3
Sci Adv. 2023 Feb 15. 9(7): eadg2997

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation.

Xuefeng Ren, Thanh N Nguyen, Wai Kit Lam, Cosmo Z Buffalo, Michael Lazarou, Adam L Yokom, James H Hurley.

The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson's disease. The structural interaction between the sole transmembrane autophagy protein, autophagy-related protein 9A (ATG9A), and components of the Unc-51-like autophagy activating kinase (ULK1) complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.4-Å x-ray crystallographic structure of the ternary structure of ATG9A carboxyl-terminal tail bound to the ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme carboxyl-terminal part of the ATG9A tail the "HORMA dimer-interacting region" (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by β sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.

DOI: https://doi.org/10.1126/sciadv.adg2997
J Cell Biol. 2023 Apr 03. pii: e202204093. [Epub ahead of print]222(4):

Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline.

Benjamin A Barad, Michaela Medina, Daniel Fuentes, R Luke Wiseman, Danielle A Grotjahn.

Cellular cryo-electron tomography (cryo-ET) enables three-dimensional reconstructions of organelles in their native cellular environment at subnanometer resolution. However, quantifying ultrastructural features of pleomorphic organelles in three dimensions is challenging, as is defining the significance of observed changes induced by specific cellular perturbations. To address this challenge, we established a semiautomated workflow to segment organellar membranes and reconstruct their underlying surface geometry in cryo-ET. To complement this workflow, we developed an open-source suite of ultrastructural quantifications, integrated into a single pipeline called the surface morphometrics pipeline. This pipeline enables rapid modeling of complex membrane structures and allows detailed mapping of inter- and intramembrane spacing, curvedness, and orientation onto reconstructed membrane meshes, highlighting subtle organellar features that are challenging to detect in three dimensions and allowing for statistical comparison across many organelles. To demonstrate the advantages of this approach, we combine cryo-ET with cryo-fluorescence microscopy to correlate bulk mitochondrial network morphology (i.e., elongated versus fragmented) with membrane ultrastructure of individual mitochondria in the presence and absence of endoplasmic reticulum (ER) stress. Using our pipeline, we demonstrate ER stress promotes adaptive remodeling of ultrastructural features of mitochondria including spacing between the inner and outer membranes, local curvedness of the inner membrane, and spacing between mitochondrial cristae. We show that differences in membrane ultrastructure correlate to mitochondrial network morphologies, suggesting that these two remodeling events are coupled. Our pipeline offers opportunities for quantifying changes in membrane ultrastructure on a single-cell level using cryo-ET, opening new opportunities to define changes in ultrastructural features induced by diverse types of cellular perturbations.

DOI: https://doi.org/10.1083/jcb.202204093
Appl Physiol Nutr Metab. 2023 Feb 14.

The role of the mechanistic target of rapamycin complex 1 in the regulation of mitochondrial adaptation during skeletal muscle atrophy under denervation or calorie restriction in mice.

Kazuki Uemichi, Takanaga Shirai, Ryunosuke Matsuno, Tomohiro Iwata, Riku Tanimura, Tohru Takemasa.

  Mechanistic target of rapamycin complex 1 (mTORC1) is a protein complex that regulates skeletal muscle protein synthesis and hypertrophy. mTORC1-mediated signaling activities are activated during denervation-induced skeletal muscle atrophy and suppressed during calorie restriction-induced atrophy. Mitochondria control the qualitative plasticity of skeletal muscles primarily through biogenesis, fusion, and fission. We recently showed that mTORC1 activation contributes toward mitochondrial homeostasis. In this study, we examined the role of mTORC1 in mitochondrial adaptation during denervation- or calorie restriction-induced skeletal muscle atrophy. Seven-week-old Institute of Cancer Research mice were subjected to 14 days of denervation or calorie restriction combined with the administration of the mTORC1 inhibitor-"rapamycin". Our results showed that although mTORC1 inhibition did not alter mitochondrial biogenesis, content and enzyme activity, it suppressed the activation of dynamin-related protein 1 (DRP1), a mitochondrial fission-related protein in denervated muscle, and reduced DRP1 expression in calorie-restricted muscle. Furthermore, calorie restriction-induced mitochondrial fragmentation was partially suppressed by mTORC1 inhibition. Taken together, our results indicate that mTORC1 activation upon denervation and inhibition upon calorie restriction contributes to qualitative changes in muscle plasticity by at least partially regulating the mitochondrial fission response.

Keywords:  mTORC1; mitochondrial dynamics; skeletal muscle atrophy

DOI:  https://doi.org/10.1139/apnm-2022-0336
Cell Death Dis. 2023 Feb 15. 14(2): 122

ERK1/2-dependent TSPO overactivation associates with the loss of mitophagy and mitochondrial respiration in ALS.

Andrea Magrì, Cristiana Lucia Rita Lipari, Pierpaolo Risiglione, Stefania Zimbone, Francesca Guarino, Antonella Caccamo, Angela Messina.

Mitochondrial dysfunction and the loss of mitophagy, aimed at recycling irreversibly damaged organelles, contribute to the onset of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting spinal cord motor neurons. In this work, we showed that the reduction of mitochondrial respiration, exactly oxygen flows linked to ATP production and maximal capacity, correlates with the appearance of the most common ALS motor symptoms in a transgenic mouse model expressing SOD1 G93A mutant. This is the result of the equal inhibition in the respiration linked to complex I and II of the electron transport chain, but not their protein levels. Since the overall mitochondrial mass was unvaried, we investigated the expression of the Translocator Protein (TSPO), a small mitochondrial protein whose overexpression was recently linked to the loss of mitophagy in a model of Parkinson's disease. Here we clearly showed that levels of TSPO are significantly increased in ALS mice. Mechanistically, this increase is linked to the overactivation of ERK1/2 pathway and correlates with a decrease in the expression of the mitophagy-related marker Atg12, indicating the occurrence of impairments in the activation of mitophagy. Overall, our work sets out TSPO as a key regulator of mitochondrial homeostasis in ALS.

DOI: https://doi.org/10.1038/s41419-023-05643-0
Hum Mol Genet. 2023 Feb 16. pii: ddad029. [Epub ahead of print]

Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery.

Brianna L Bauer, Kristy Rochon, Jasmine C Liu, Rajesh Ramachandran, Jason A Mears.

Patient mutations have been identified throughout dynamin-related protein 1 (Drp1), the key protein mediator of mitochondrial fission. These changes generally impact young children and often result in severe neurological defects and, in some instances, death. Until now, the underlying functional defect leading to patient phenotypes has been largely speculative. We therefore analyzed six disease-associated mutations throughout the GTPase and middle domains of Drp1. The middle domain (MD) plays a role in Drp1 oligomerization, and three mutations in this region were predictably impaired in self-assembly. However, another mutant in this region (F370C) retained oligomerization capability on pre-curved membranes despite being assembly-limited in solution. Instead, this mutation impaired membrane remodeling of liposomes, which highlights the importance of Drp1 in generating local membrane curvature before fission. Two GTPase domain mutations were also observed in different patients. The G32A mutation was impaired in GTP hydrolysis both in solution and in the presence of lipid but remains capable of self-assembly on these lipid templates. The G223V mutation also exhibited decreased GTPase activity and was able to assemble on pre-curved lipid templates; however, this change impaired membrane remodeling of unilamellar liposomes similar to F370C. This demonstrates that the Drp1 GTPase domain also contributes to self-assembly interactions that drive membrane curvature. Overall, the functional defects caused by mutations in Drp1 are highly variable even for mutations that reside within the same functional domain. This study provides a framework for characterizing additional Drp1 mutations to provide a comprehensive understanding of functional sites within this essential protein.

DOI: https://doi.org/10.1093/hmg/ddad029
J Biol Chem. 2023 Feb 14. pii: S0021-9258(23)00150-3. [Epub ahead of print] 103018

Mitochondrial respiration reduces exposure of the nucleus to oxygen.

Mateus Prates Mori, Rozhin Penjweini, Jin Ma, Greg Alspaugh, Alessio Andreoni, Young-Chae Kim, Ping-Yuan Wang, Jay R Knutson, Paul M Hwang.

  The endosymbiotic theory posits that ancient eukaryotic cells engulfed O2-consuming prokaryotes, which protected them against O2 toxicity. Previous studies have shown that cells lacking cytochrome c oxidase (COX), required for respiration, have increased DNA damage and reduced proliferation, which could be improved by reducing O2 exposure. With recently developed fluorescence lifetime microscopy (FLIM)-based probes demonstrating that the mitochondrial compartment has lower [O2] than the cytosol, we hypothesized that the perinuclear distribution of mitochondria in cells may create a barrier for O2 to access the nuclear core, potentially affecting cellular physiology and maintaining genomic integrity. To test this hypothesis, we utilized myoglobin (MB)-mCherry FLIM O2 sensors without subcellular targeting ("cytosol") or with targeting to the mitochondrion or nucleus for measuring their localized O2 homeostasis. Our results showed that, similar to the mitochondria, the nuclear [O2] was reduced by ∼20-40% compared to the cytosol under imposed O2 levels of ∼0.5-18.6%. Pharmacologic inhibition of respiration increased nuclear O2 levels, and reconstituting O2 consumption by COX reversed this increase. Similarly, genetic disruption of respiration by deleting SCO2, a gene essential for COX assembly, or restoring COX activity in SCO2-/- cells by transducing with SCO2 cDNA also replicated these changes in nuclear O2 levels. The results were further supported by the expression of genes known to be affected by cellular O2 availability. Our study reveals the potential for dynamic regulation of nuclear O2 levels by mitochondrial respiratory activity, which in turn could affect oxidative stress and cellular processes such as neurodegeneration and aging.

Keywords:  Classification: Cell Biology; Metabolism; hypoxia; mitochondria; nucleus; oxygen; respiration

DOI:  https://doi.org/10.1016/j.jbc.2023.103018
Eur J Cell Biol. 2023 Feb 10. pii: S0171-9335(23)00012-2. [Epub ahead of print]102(2): 151297

Mitochondria transfer reverses the inhibitory effects of low stiffness on osteogenic differentiation of human mesenchymal stem cells.

Shaoyang Ma, Rui Ding, Jiao Cao, Zhongbo Liu, Ang Li, Dandan Pei.

  Microenvironment biophysical factors such as matrix stiffness can noticeably affect the differentiation of mesenchymal stem cells (MSCs). In this mechanobiology transduction process, mitochondria are shown to be an active participant. The present study aims to systematically elucidate the phenotypic and functional changes of mitochondria during the stiffness-mediated osteogenic differentiation. Additionally, the effect of mitochondria transfer on the osteogenesis of impaired MSCs caused by stiffness was investigated. Human periodontal ligament stem cells (PDLSCs) were used as model cells in the current study. Low stiffness restrained the cell spreading and significantly inhibited the proliferation and osteogenic differentiation of PDLSCs. Mitochondria of PDLSCs cultured on low stiffness exhibited shorter length, rounded shape, fusion/fission imbalance, ROS and mitophagy level increase, and ATP production reduction. The inhibited mitochondria function and osteogenic differentiation capacity were recovered to near-normal levels after transferring the mitochondria of PDLSCs cultured on the high stiffness. This study indicated that low matrix stiffness altered the mitochondrial morphology and induced systematical mitochondrial dysfunction during the osteogenic differentiation of MSCs. Mitochondria transfer was proved to be a feasible technique for maintaining MSCs function in vitro by reversing the osteogenesis ability.

Keywords:  Matrix stiffness; Mitochondria; Mitochondria transfer; Osteogenesis; PDLSCs

DOI:  https://doi.org/10.1016/j.ejcb.2023.151297